Congestive heart failure (CHF) is a major market opportunity for therapeutics that targets the fundamental etiology of the ventricular injury. Although the pathogenesis of CHF is complex, recent data suggest an inflammatory basis secondary to free radical generation by the purine degradative enzyme xanthine oxidase (XO). In the well-established pacing dog model, which produces a dilated cardiomyopathy and many of the classic features of CHF, XO activity is 4-fold increased and the weak XO inhibitor allopurinol increases dP/dt(max), preload-recruitable stroke work, and ventricular elastance. In heart failure dogs, but not controls, allopurinol decreases MVO2 and substantially increases mechanical efficiency. Taken together, these data indicate that XO inhibition is uniquely inotropic, increasing myocardial contractility while simultaneously reducing cardiac energy requirements. The resultant boost in myocardial contractile efficiency may prove beneficial in the treatment of clinical CHF. The market for allopurinol is limited by its infrequent but severe side-effects. We now report the discovery of a non-purine class of XO inhibitors that is 1,000-fold more potent than allopurinol. Preliminary data confirm that a prototype of this class profoundly reduces inflammation in experimental models of acute lung injury and enterocolitis. The central objective of this Phase I grant proposal is to establish in vivo proof of principle that the lead candidate dose-dependently improves contractile function in the classic dog model of CHF induced by chronic pacing. We will then define the pharmacodynamic profile of XO therapy, begun after the establishment of CHF. Cardiac contractility will be assessed using left ventricular pressure-volume analysis, dP/dT, stroke volume, and ejection fraction. The classic weak XO inhibitor allopurinol will be included in all studies as a reference standard. We expect that our lead non-purine ultrapotent XO inhibitor will dose-dependently improve dP/dT, with an ED5O greater than 2-fold greater than allopurinol. PROPOSED COMMERCIAL APPLICATION: Sale of $500 million per annum are anticipated in the US alone, based upon an estimate of a 1% incidence of CHF in the general population (=2.5 million potential subjects), a 10% market penetration, and an annual expenditure per patient of $2,000. The worldwide market (developed countries only) is four times larger. Given the intoleerance for allopurinol in 10% of patients, and the current absence of a second-line medication, we expect the market acceptance of a safe and effective alternative XO inhibitor to be achieved rapidly over a five year period. We believe the high price point ($6 per day) is amply justified by the lack of an alternative to allopurinol. Estimated worldwide gross sales revenues after market entry and maturation (ca. 4 years after FDA approval) are expected to equal $1-2 billion per annum.